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Free heme regulates placenta growth factor through NRF2-antioxidant response signaling.

ABSTRACT: Free heme activates erythroblasts to express and secrete Placenta Growth Factor (PlGF), an angiogenic peptide of the VEGF family. High circulating levels of PlGF have been associated in experimental animals and in patients with sickle cell disease with echocardiographic markers of pulmonary hypertension, a life-limiting complication associated with more intense hemolysis. We now show that the mechanism of heme regulation of PlGF requires the contribution of the key antioxidant response regulator NRF2. Mimicking the effect of heme, the NRF2 agonist sulforaphane stimulates the PlGF transcript level nearly 30-fold in cultured human erythroblastoid cells. Heme and sulforaphane also induce transcripts for NRF2 itself, its partners MAFF and MAFG, and its competitor BACH1. Furthermore, heme induction of the PlGF transcript is significantly diminished by the NRF2 inhibitor brusatol and by siRNA knockdown of the NRF2 and/or MAFG transcription factors. Chromatin immunoprecipitation experiments show that heme induces NRF2 to bind directly to the PlGF promoter region. In complementary in vivo experiments, mice injected with heme show a significant increase in their plasma PlGF protein as early as 3?h after treatment. Our results reveal an important mechanism of PlGF regulation, adding to the growing literature that supports the pivotal importance of the NRF2 axis in the pathobiology of sickle cell disease.

SUBMITTER: Kapetanaki MG

PROVIDER: S-EPMC6848791 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Free heme regulates placenta growth factor through NRF2-antioxidant response signaling.

Kapetanaki Maria G MG Gbotosho Oluwabukola T OT Sharma Deva D Weidert Frances F Ofori-Acquah Solomon F SF Kato Gregory J GJ

Free radical biology & medicine 20190810

Free heme activates erythroblasts to express and secrete Placenta Growth Factor (PlGF), an angiogenic peptide of the VEGF family. High circulating levels of PlGF have been associated in experimental animals and in patients with sickle cell disease with echocardiographic markers of pulmonary hypertension, a life-limiting complication associated with more intense hemolysis. We now show that the mechanism of heme regulation of PlGF requires the contribution of the key antioxidant response regulator ...[more]

PMID: 31408727

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Project description:BackgroundResveratrol, a plant phenol, affords protection against inflammation and oxidative stress. The objective of this study was to investigate the effects of dietary resveratrol supplementation during pregnancy and lactation on the antioxidant status of sows and piglets and on antioxidant gene expression and pathway in placenta.MethodsForty sows were allotted to 2 dietary treatments 20 d after breeding. Sows were fed a control diet and a control diet with 300 mg/kg resveratrol. Oxidative stress biomarkers and antioxidant enzymes were measured in the placenta, milk, and plasma of sows and piglets. Antioxidant gene expression and protein expression of Kelch-like ECH-associated protein 1-Nuclear factor E2-related factor 2 (Keap1-Nrf2), nuclear factor kappa B-p65 (NFκB-p65) and sirtuin1 (Sirt1) were quantified in the placenta.ResultsDietary resveratrol increased the litter and piglets weaning weights. Antioxidant status in the milk, placenta and plasma of sows and piglets was partially improved by dietary resveratrol. In placenta, Nrf2 protein expression was increased and Keap1 protein expression was decreased by dietary resveratrol. The mRNA expression of antioxidant genes including catalase (CAT), glutathione peroxidase 1 (GPX1), GPX4, superoxide dismutase 1 (SOD1) and heme oxygenase 1 (HO1), and phase 2 detoxification genes, including glutamate-cysteine ligase modifier (GCLM), microsomal glutathione S-transferase 1(MGST1) and UDP glucuronosyltransferase family 1 member A1 (UGT1A1), was increased by dietary resveratrol. Dietary resveratrol also increased Sirt1 and phosphorylated NFκB-p65 protein expression in the placenta. We failed to observe any influences of dietary resveratrol on pro-inflammatory cytokine levels, including those of interleukin 1β (IL-1β), IL-6, IL-8 and tumor necrosis factor α (TNF-α). However, we observed that the mRNA expression of IL-8 in placenta was reduced by maternal resveratrol. In addition, dietary resveratrol showed interactive effects with day of lactation on activities of SOD and CAT and levels of malonaldehyde (MDA) and hydrogen peroxide (H2O2) in milk.ConclusionsDietary resveratrol supplementation during pregnancy and lactation improves the antioxidant status of sows and piglets, which is beneficial to the reproductive performance of sows. Dietary resveratrol regulates placental antioxidant gene expression by the Keap1-Nrf2 pathway and Sirt1 in placenta.

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Free heme regulates placenta growth factor through NRF2-antioxidant response signaling.

Publications

Free heme regulates placenta growth factor through NRF2-antioxidant response signaling.

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